The invention concerns a low coherence interferometric (LCI) method for detecting plaques. For example, a method and apparatus for the analysis and detection of atheromas and/or atherosclerotic plaques in arterial walls. More particularly, in one embodiment, a methodology and system for detecting and evaluating vulnerable atherosclerotic plaques in a blood vessel. Further, measurement of the interface between the plaque and lipid pool between the plaque and the artery and measurement the thickness of the plaque with a high accuracy. An application area of interest is that of the diagnosis and management of cardiovascular diseases (CVD).
Coronary Heart Disease (CHD) accounts for approximately fifty percent of the death toll attributed to CVD. Despite major advances in the treatment of coronary heart disease patients, a large number of victims of CHD who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the catastrophic event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. Vulnerable plaques have been defined as any atherosclerotic plaque with high likelihood of thrombotic complications and rapid progression. Researchers have found that many people who experience heart attacks do not have arteries that have been severely narrowed by plaque. In fact, vulnerable plaque may be buried inside the arterial wall. It has also been found that in these individuals, that vulnerable plaque manifested itself as more than just debris clogging an artery, but that it was filled with different cell types that induce blood clotting. One particularly lethal type of vulnerable plaque is generated through an inflammation process, leading to the formation of a large lipid core inside the artery wall, covered by a thin fibrous cap. When this thin covering over the plaque cracks and bleeds, it spills the contents of the vulnerable plaque into the bloodstream, creating clots large enough to block the artery.
Therefore, there is considerable interest in the identification of plaques prior to the occurrence of thrombosis. Early detection would enhance therapies, while leading to trials of novel preventive measures. Multiple new technologies to improve characterization of plaque in patients are under development. These techniques seek to identify the histologic features, of plaques suspected to represent vulnerability, and provide additional information that heretofore has not been available. Data on structure, composition, deformability, pathophysiology, metabolism, temperature, and the like will enhance characterization. The additional information is key to the accurate detection, characterization and management of vulnerable plaque, with positive outcome for the patients.
Peripheral Vascular Disease (PVD) affects 8 to 12 million Americans and is associated with significant disability and mortality. PVD is a condition in which the arteries that carry blood to the arms or legs become narrowed or clogged. This narrowing or clogging interferes with the normal flow of blood, sometimes causing pain but often exhibiting no symptoms at all. The most common cause of PVD is atherosclerosis, a gradual process in which cholesterol and scar tissue build up, forming a substance called “plaque” that clogs the blood vessels. In some cases, PVD may be caused by blood clots that lodge in the arteries and restrict blood flow. In extreme cases, untreated PVD can lead to gangrene, a serious condition that may require amputation of a leg, foot or toes.
In general, atheromatous or atherosclerotic plaques characteristically comprise a fibrous cap surrounding a central core of extracellular lipids and debris located in the central portion of the thickened vessel intima, which is known as the “atheroma”. On the luminal side of the lipid core, the fibrous cap is comprised mainly of connective tissues, typically a dense, fibrous, extracellular matrix made up of collagens, elastins, proteoglycans and other extracellular matrix materials. In the case of arterial plaques the chronically stenotic plaque in which calcified material builds up in the artery to cause occlusion as discussed above may readily be distinguished from the rupture-prone vulnerable plaque, which consists of a thin fibrous cap and a large lipid core in the wall of the artery. The stenotic plaque is easily detected with MRI, ultrasound, and other diagnostic techniques. Once detected, it is opened up using a stent within a catheter.
With an active atheromatous or atherosclerotic plaque, at the edges of the fibrous cap overlying the lipid core comprises the shoulder region and is enriched with macrophages. The macrophages continually phagocytose oxidized LDL through scavenger receptors, which have a high ligand specificity for oxidized LDL. Continuous phagocytosis results in the formation of foam cells, a hallmark of the atherosclerotic plaque. Foam cells, together with the binding of extracellular lipids to collagen fibers and proteoglycans, play an important role in the formation and growth of the lipid-rich atheroma.
Examination of atheromatous/atherosclerotic plaques has revealed substantial variations in the thickness of fibrous caps, the size of the atheromas, the extent of dystrophic calcification, and the relative contribution of major cell types. Atheromatous plaques include a significant population of inflammatory cells, such as monocytes or macrophages and T lymphocytes. The emigration of monocytes into the arterial wall, and their subsequent differentiation into macrophages and ultimately foam cells, remains one of the earliest steps in plaque formation. Once there, these cells play a critical role in secreting substances that further contribute to atherosclerosis.
The causative agent of acute coronary syndrome is fissure, erosion or rupture of a specific kind of atheromatous plaque known as a “vulnerable plaque.” It has been determined that vulnerable plaques are responsible for the majority of heart attacks, strokes, and cases of sudden death. A vulnerable plaque is structurally and functionally distinguishable from a stable atheromatous plaque. For example, a vulnerable plaque is characterized by an abundance of inflammatory cells (e.g., macrophages and/or T cells), a large lipid pool, and a thin fibrous cap. Pathologic studies have also provided a further understanding of why vulnerable plaques have a higher propensity for rupture than other atheromatous plaques. The thickness and integrity of the fibrous cap overlying the lipid-rich core is a principal factor in the stability of the plaque. Generally, atheromatous plaques prone to rupture can be characterized as having thinner fibrous areas, increased numbers of inflammatory cells (e.g., macrophages and T cells), and a relative paucity of vascular smooth muscle cells. Vascular smooth muscle cells are the major source of extra cellular matrix production, and therefore, the absence of vascular smooth muscle cells from an atheromatous plaque contributes to the lack of density in its fibrous cap.
While the fibrous tissue within the cap provides structural integrity to the plaque, the interior of the atheroma is soft, weak and highly thrombogenic. It is rich in extracellular lipids and substantially devoid of living cells, but bordered by a rim of lipid-laden macrophages. The lipid core is a highly thrombogenic composition, rich in tissue factor, which is one of the most potent procoagulants known. The lesional macrophages and foam cells produce a variety of procoagulant substances, including tissue factor. The fibrous cap is the only barrier separating the circulation from the lipid core and its powerful coagulation system designed to generate thrombus. Essentially, the rapid release of procoagulants into the blood stream at the site of rupture forms an occlusive clot, inducing acute coronary syndrome. Thus, the thinner the fibrous cap, the greater the instability of the thrombogenic lipid core and the greater the propensity for rupture and thrombosis. Generally, it has been determined that the critical thickness of the cap is of the order of 70 microns.
Common methods of plaque detection include angiography and angioscopy. Except in rare circumstances, angiography gives almost no information about the characteristics of plaque components. However, angiography is only sensitive enough to detect hemodynamically significant lesions (>70% stenosis), which account for approximately 33% of acute coronary syndrome cases. Angioscopy is a technique based on fiber-optic transmission of visible light that provides a small field of view with relatively low resolution for visualization of interior surfaces of plaque and thrombus. Because angioscopic visualization is limited to the surface of the plaque, it is generally insufficient for use in detecting actively forming atheromatous plaques and/or determining vulnerable plaques.
Several methods are being investigated for their ability to identify atheromatous plaques. One such method, intravascular ultrasound (“IVUS”) uses miniaturized crystals incorporated at catheter tips and provides real-time, cross-sectional and longitudinal, high-resolution images of the arterial wall with three-dimensional reconstruction capabilities. IVUS can detect thin caps and distinguish regions of intermediate density (e.g., intima that is rich in smooth muscle cells and fibrous tissue) from echolucent regions, but current technology does not determine which echolucent regions are composed of cholesterol pools rather than thrombosis, hemorrhage, or some combination thereof. Moreover, the spatial resolution (i.e., approximately 100 μm) does not distinguish the moderately thinned cap from the high risk cap (i.e., approximately 25-75 μm) and large dense calcium deposits produce acoustic echoes which “shadow” so that deeper plaque is not imaged.
Intravascular thermography is based on the premise that atheromatous plaques with dense macrophage infiltration give off more heat than non-inflamed plaque. The temperature of the plaque is inversely correlated to cap thickness. However, thermography may not provide information about eroded but non-inflamed lesions, vulnerable or otherwise, having a propensity to rupture.
Raman spectroscopy utilizes Raman effect: a basic principle in photonic spectroscopy named after its inventor. Raman effect arises when an incident light excites molecules in a sample, which subsequently scatter the light. While most of this scattered light is at the same wavelength as the incident light, some is scattered at a different wavelength. This shift in the wavelength of the scattered light is called Raman shift. The amount of the wavelength shift and intensity depends on the size, shape, and strength of the molecule. Each molecule has its own distinct “fingerprint” Raman shift. Raman spectroscopy is a very sensitive technique and is capable of reporting an accurate measurement of chemical compounds. Conceivably, the ratio of lipid to proteins, such as collagen and elastin, might help detect vulnerable plaques with large lipid pools. However, it is unlikely that actively forming and/or vulnerable plaques will be reliably differentiated from stable plaques based solely on this ratio.
Radiation-based methods for detection of diseased tissue are also known in the art. Some devices include an ion-implanted silicon radiation detector located at the tip of a probe with a preamplifier contained within the body of the probe, and connected to the detector as well as external electronics for signal handling. Another device provides radio-pharmaceuticals for detecting diseased tissue, such as a cancerous tumor, followed by the use of a probe with one or more ion-implanted silicon detectors at its tip to locate the radio labeled diseased tissue; the detector is preferentially responsive to beta emissions.
Optical coherence tomography (“OCT”) measures the intensity of reflected near-infrared light from tissue. OCT is an application of to form 3D images. OCT provides images with high resolutions that are approximately 10 to 20 times higher than that of IVUS, which facilitates detection of a thin fibrous cap. Advantageously, while other methodologies may exhibit the capability to detect the presence of lipids within the vessel wall, OCT techniques have been shown to exhibit the spatial resolution sufficient for resolving the parameters directly responsible for plaque ruptures. Unfortunately, OCT is an imaging technique and, as a result, is computationally intensive and very time consuming. The resulting images from OCT require skilled interpretation for the detection of vulnerable plaques.
Low Coherence Interferometry (LCI) is an optical technique that allows for accurate, analysis of optical interfaces, and is very adaptable to the analysis of the scattering properties of heterogeneous optical media such as layered biological tissue. Furthermore, the interface between two regions in biological tissues exhibiting different optical characteristics is characterized by change in scattering, absorption, and refractive index characteristics. Of particular interest, are sensitive methods to measure the important features of the signal at the discontinuity e.g., such as between a fibrous cap and lipid pool. In LCI, light from a broad bandwidth light source is first split into sample and reference light beams which are both retro-reflected, from a targeted region of the sample and from a reference mirror, respectively, and are subsequently recombined to generate an interference signal having maxima at the locations of constructive interference and minima at the locations of destructive interference. The interference signal is then employed to evaluate the characteristics of the sample. LCI exhibits very high resolution as the detectable interference occurs only if the optical path difference between them is less than the coherence length of the source. LCI can be used in the detection and characterization of blockage sites in peripheral arteries. The LCI interferometer can be made out of optical fibers, and therefore can be easily integrated with catheters used by interventional radiologists to open blood vessels. Unfortunately, current LCI techniques, such as OCT, rely on amplitude measurements of the interferences signal and may lack the high resolution required for accurate detection and characterization of vulnerable plaques.
The term “biological sample” denotes a body fluid or tissue of a living organism. Biological samples are generally optically heterogeneous, that is, they contain a plurality of scattering centers scattering irradiated light. In the case of biological tissue, especially skin tissue, the cell walls and other intra-tissue components form the scattering centers.
In spite of these endeavors, attempts to make available an effective sensor for practical operation to detect vulnerable plaque have thus far, proved inadequate. What is needed in the art is a new approach for LCI-based plaque detection and characterization based on the measurement of the phase of the interferometric signal to facilitate accurate detection and characterization of atheromatic/atherosclerotic plaques and particularly vulnerable plaques.